N-haloalkanoyl-2-nitrodiphenyl-amines



United States Patent M 3,510,516 N-HALOALKANOYL-2-NlTRODIPHENYL-AMINES John W. Schulenberg, Bethlehem, N.Y., assignor to Sterling Drug Inc., New York, N.Y., a corporation of Delaware No Drawing. Application Oct. 21, 1966, Ser. No. 588,339,

now Patent No. 3,415,839, which is a continuation-inpart of application Ser. No. 404,952, Oct. 19, 1964. Divided and this application Mar. 29, 1968, Ser. No.

Int. Cl. c07 87/54 US. Cl. 260-562 '2 Claims ABSTRACT OF THE DISCLOSURE 1-R-2-R'-benzimidazole 3-oxides, where R and R are lower-alkyl or phenyl, at least one of R and R being phenyl, having hyperglycemic and tranquillizing activities, are prepared by hydrogenating the appropriate 2-nitroanilines substituted on nitrogen by the groups R and COR, where R" is lower-alkyl, phenyl, l-chloro-lower-alkyl or 1,1-dichloro-1ower-alkyl.

This application is a division of application Ser. No. 588,339, filed Oct. 21, 1966, now US. Pat. 3,415,839, which in turn is a continuation-in-part of application Ser. No. 404,952, filed Oct. 19, 1964, now abandoned.

This invention relates to new heterocyclic compounds and in particular is concerned with 1,2-disubstituted-benzimidazole 3-oxides and the preparation thereof, including intermediates therein.

The compounds of the invention are of the following structure:

wherein R and R' are lower-alkyl or phenyl, at least one of R and R being phenyl. The lower-alkyl group preferably has from one to five carbon atoms.

The compounds of the invention are prepared by catalytically hydrogenating a compound of the formula 3,510,516 Patented May 5, 1970 wherein R is l-chloro-lower-alkyl or 1,1-dichloro-loweralkyl.

The structures of the compounds of the invention were established by elementary analysis, and by ultraviolet, infrared and nuclear magnetic resonance spectra, which showed the absence of a carbonyl group. Further structure proof was provided by the fact that the product derived from hydrogenation of N-chloroacetyl-Z-nitrodiphenylamine was not identical with another possible structure, l-phenylbenzimidazole-Z-methanol, prepared by an alternative synthesis (cyclization of 2-anilino-2- hydroxyacetanilide) Pharmacological evaluation has shown that the compounds of formula I possess hyperglycemic and psychomotor depressant properties thus indicating their usefulness in regulating the blood sugar content and as tranquillizers.

The compounds of Formula I are useful both in free base form and in acid-addition salt form, and both forms are within the purview of the invention and are considered to be one and the same invention.

The following examples will further illustrate the invention.

EXAMPLE 1 (a) N-chloroacetyl-2-nitrodiphenylamine [111; R is CH Cl].A mixture of 64.2 g. (0.3 mole) of Z-nitrodiphenylamine, 67.5 g. (45 ml., 0.6 mole) of chloroacetyl chloride and ml. of toluene was refluxed for four and three-quarters hours. The toluene was removed in vacuo and the residue recrystallized from ethanol to give 74.5 g. of N-chloroacetyl-2-nitrodiphenylamine, yellow prisms, M.P. 122124 C. (uncorr.); ultraviolet maximum at 232 m (e=l6,300); infrared absorption peak at 5.9M.

N-chloroacetyl 2 nitrodiphenylamine when administered intraperitoneally to mice at a dose level of 100 mg./ kg. showed an 82% decrease in spontaneous activity.

By replacing the chloroacetyl chloride in the preceding preparation by a molar equivalent amount of a-chloropropionyl chloride, u-chloroisobutyryl chloride or a-chlorocapropyl chloride, there can be obtained, respectively, N- a-chloropropionyl) -2-nitrodiphenylamine, N- oc-ChlO- roisobutyryl)-2-nitrodiphenylamine, or N-(a-ohlorocaproyl) -2-nitrodiphenylamine.

By replacing the 2-nitrodiphenylamine in the preceding preparation by a molar equivalent amount of 2-nitro- 4'-methyldiphenylarnine, there can be obtained N-chloroacetyl-2-nitro-4'-methydiphenylamine.

(b) 1-phenyl-2-methylbenzimidazole 3-oxide [1; R is C H R is CH ].A solution of 14.55 g. (0.05 mole) of N-chloroacetyl-Z-nitrodiphenylamine in 225 ml. of absolute ethanol was hydrogenated at room temperature in the presence of 200 mg. of platinum oxide. After one hour the requisite three molar equivalents of hydrogen had been absorbed, and the hydrogenation was terminated and the mixture filtered. The hydrogenation was repeated starting with 13.0 g. of N-chloroacetyl-2-nitrodiphenylamine, and the two runs were combined and concentrated to a small volume. The product was crystallized from acetone containing a little absolute ether to give 17.0 g. of 1-phenyl-2-methylbenzirnidazole 3-oxide in the form of its hydrochloride salt, prisms, M.P. 212.0 213.6 C. (dec.) (corn); ultraviolet maxima at 249, 272 and 279 m (6 6080, 7300 and 7700, respectively), and

shoulder at 289 Ill 1.; infrared absorption peaks at 3.30, 4.50, 6.22, 6.28, 6.60, 6.71, 6.85, 7.34, 7.57, 7.98 and 8.17 1.

AnaIysis.Calcd. for C H N O.HCl (percent): C, 64.49; H, 5.02; N, 10.75. Found (percent): C, 64.79; H, 4.99; N, 10.61.

1-phenyl-2-methylbenzimidazole 3-oxide was also obtained when N-chloroacetyl-2-nitrodiphenylamine was hydrogenated in the presence of palladium-on-carbon catalyst instead of platinum oxide catalyst.

A sample of the hydrochloride salt was dissolved in water, excess potassium bicarbonate added, and the base extracted with chloroform. The chloroform extracts were washed with water, dried and concentrated, and the residue recrystallized from ethyl acetate to give l-phenyl-2- methylbenzimidazole 3-oxide in the form of colorless prisms, M.P. 159-167 C. (uncorr.); infrared absorption peaks at 3.32, 6.28, 6.64, 6.83, 7.35, 7.70, 8.03 and 824 Analysis.-Calcd. for C H N O (percent): C, 74.99; H, 5.38; N, 12.49. Found (percent): C, 75.42; H, 5.14; N, 12.39.

By replacing the N-chloroacetyl-2-nitrodiphenylamine in preparation (b) above by a molar equivalent amount of N-(a-chloropropionyl) 2 nitrodiphenylamine, N-(achloroisobutyryl) 2 nitrodiphenylamine, N-(a-ChlOIO- caproyl) 2 nitrodiphenylamine, or N-chloroacetyl-Z- nitro-4'-methyldiphenylamine, there can be prepared, respectively, l-phenyl 2 ethylbenzimidazole 3-oxide, 1- phenyl 2 isopropylbenzimidazole 3-oxide, 1-pheny1-2- pentylbenzimidazole 3-oxide, or l-(p-tolyl)-2-methylbenzimidazole 3-oxide.

l-phenyl-2-methylbenzimidazole 3-oxide in the form of its hydrochloride salt when administered at 100 mg./ kg. orally to fasted male rats caused a 49% increase in the blood glucose level.

(c) 1-phenylbenzimidazole-2-methan0l.A mixture of 5.9 g. (0.024 mole) of 2'-anilino-2-hydroxyacetanilide (M.P. 143l50 C.) (prepared from N-phenyl-o-phenylenediamine and glycolic acid), 5 g. (0.026 mole) of ptoluenesulfonic acid hydrate and 250 ml. of toluene was slowly distilled over a three hour period. The reaction mixture was cooled, aqueous sodium hydroxide added and the freed base extracted with ether. Solvent removal left a brown solid which was recrystallized to give 4.3 g. of 1-phenylbenzimidazole-2-methanol, M.P. 131.4- 132.4 C. (corr.).

Analysis.-Calcd. for C H N O (percent): N, 12.49. Found (percent): N, 12.38.

Ethanolic hydrogen chloride was added to a solution of 1-phenylbenzimidazole-Z-methanol in acetone. The solid which separated was collected and recrystallized from an isopropyl alcohol-acetone mixture to give 1- phenylbenzimidazole-2-methanol in the form of its hydrochloride salt, colorless needles, M.P. 192-197 C. (corr.). A mixture melting point with the hydrochloride salt of 1-phenyl-2-methylbenzimidazole 3-oxide showed a marked depression.

Analysis.-Calcd. for C H CIN O (percent): 10.75. Found (percent): N, 10.53.

1-phenylbenzimidazole-Z-methanol was found to be bacteriostatic in vitro against Cl. welchii at a concentraion of 0.002 mg. per ml.

EXAMPLE 2 (a) N-(2,2-dichloroacetyl)-2-nitrodiphenylamine [III; R" is CHCl ].A solution of 21.4 g. (0.1 mole) of o-nitrodiphenylamine and 29.5 g. (0.2 mole) of dichloroacetyl chloride in 30 ml. of toluene was refluxed for 24 hours. Ethanol was then added and the mixture cooled to furnish 22.8 g. of solid, M.P. 143-145 C. The latter was recrystallized three times from absolute ethanol to give. 10.5 g. of N-(2,2-dichloroacetyl)-2-nitrodiphenylamine, tan solid, M.P. 152-154 C.

Analysis.-Calcd. for C H CI N O (percent): C,

4 51.71; H, 3.10; N, 8.61. Found (percent): C, 51.80; H, 3.25; N, 8.79.

(b) N-(2,2-dichloroacetyl)-2-nitrodiphenylamine was hydrogenated according to the procedure of Example 1, part (b) to give a 57% yield of 1-phenyl-2-methylbenzimidazole in the form of its hydrochloride salt, M.P. 201-205 0., identical with the product of Example 1, part (b).

EXAMPLE 3 1,2-diphenylbenzimidazole 3-oxide [I; R and R are C H ].N-benzoyl-2-nitrodiphenylamine (10.29 g.) in ml. of absolute ethanol containing 0.034 mole of hydrogen chloride was hydrogenated in the presence of 100 mg. of platinum oxide. After the uptake of hydrogen had ceased, the reaction mixture Was filtered and the filtrate concentrated to remove the solvent. The residue was recrystallized from isopropyl alcohol to give 7.84 g. of 1,2-diphenylbenzimidazole 3-oxide in the form of its hydrochloride salt, light pink solid, M.P. 253-254 C. (dec.). A sample of the hydrochloride salt was treated with alkali to give the free base, M.P. 192-195 C. (dec.) when recrystallized from ethyl acetate.

Analysis.-Calcd. for C H N O (percent): C, 79.71; H, 4.93; N, 9.79. Found (percent): C, 79.98; H, 5.38; N. 9.79.

Similarly, N- (p-methoxybenzoyl) -2-nitrodiphenylamine can be hydrogenated to produce 1-phenyl-2-(p-methoxyphenyl)benzimidazole 3-oxide.

EXAMPLE 4 1-methyl-2-phenylbenzimidazole 3-o-Xide [I;-R is CH R is C H was prepared by hydrogenating N-benzoyl- N-methyl-Z-nitroaniline according to the procedure of Example 3, and was obtained in the form of its hydrochloride salt, M.P. 248-250.5 C. (dec.) when recrystallized from absolute ethanol.

Analysis.Calcd. for C H N -HC1 (percent): C, 59.17; H, 6.07; N, 15.34. Found (percent): C, 58.95; H, 6.08; N, 14.77.

I claim:

1. A compound of the formula -NCO-R phenyl wherein R is 1,1-dichlorolower-alkyl, said 1,1-dichlorolower-alkyl, said 1,1-dichloro-lower-alkyl having from one to five carbon atoms.

2. N-(2,2-dichloroacetyl) 2 nitrodiphenylamine, according to claim 1, wherein R" is dichloromethyl.

References Cited FOREIGN PATENTS 473,526 3/1929 Germany.

OTHER REFERENCES Clark et al., Biochem, Jour., vol. 55, pp. 839-43 (1953). Forest et al., J. Chem. Soc., (London) pp. 454-6 (1946).

Goldberg, Chem. Abst., vol. 2, p. 535 (1908). Goldberg, Berichte, vol. 4, pp. 4541-46 (1907). Verderame, J. Pharm. Sci., vol. 50, pp. 312-15 (1961). Lutskii et al., Chem. Abstr., vol. 56, col. 3383 (1962). Wright, Chem. Rev., vol. 48, pp. 458-62 (1951).

HENRY R. JILES, Primary Examiner H. I. MOATZ, Assistant Examiner U.S. Cl. X.R.

3 33 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3 510, 516 Dated May 5, 1970 InventorQs) John W. Schulenberg It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 1, insert the following paragraph between lines 49-50: "The substitution of simple moieties on the benzene ring of the benzimidazole nucleus, and/or on the groups R and B when they stand for phenyl does not adversely affect the pharmacological activity of the compounds. Illustrative but not limitative examples of such simple moieties are lower-alkyl, lower-alkoxy and halo.

Column 4, line 48, Claim 1, "l,l-dichlorolower" should read 1,1-d1chloro-1owerline 49, delete said l,l-dichloro-lower-alkyl". 4

Signed and sealed this 14th day of May 1 971 (SEAL) Attest:

EDWARD M.FLETCHER,JR. WILLIAM E. SCHUYLER, JR Attesting Officer Commissioner of Patents 

